Thyroid Hormone Profile in Ambulatory Heart Failure Patients Attending Adult Outpatient Clinic at Kenyatta National Hospital

Thyroid Hormone Profile in Ambulatory Heart Failure Patients Attending Adult Outpatient Clinic at Kenyatta National Hospitaliv
ACKNOWLEDGEMENT
I would like to acknowledge and thank my supervisors, Prof M. D Joshi, Prof E. O. Amayo and
Dr. Wanjiku Kagima for their mentorship during the writing of this dissertation. Their continued
patience, wisdom, and guidance made this work possible.
I would also like to appreciate Mr. Francis W. Maina, Senior Lecturer in the department of
Human Pathology, University of Nairobi (UoN) for collaboration in the performance of the
thyroid function tests to ensure quality assurance.
Thank you to all members of faculty of the department of clinical medicine and therapeutics for
their encouragement and support.
I also thank all the patients who consented to participate in this study, all the staff of the cardiac
clinic and the staff at the UoN Paediatrics laboratory. I recognize all my colleagues for their
encouragement and support.
To my research assistants, Collins Kariuki, Benson Mutiso and Samwel Gatimu, thank you.
To all my friends thank you for the encouragement.
I am greatly indebted to my parent’s Dr C.E Muyodi and Ms Sylvia Wewa for their guidance,
support, love and prayers, my brother Isaac for his prayers and encouragement and special thanks
to my sister Maureen, for walking with me throughout this journey.
Lastly, thanks be to God Almighty. Through Him all things are possible.
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Table 1. Diagnostic criteria for hyperthyroidism subtypes ............................................................. 5
Table 2. Summary of prevalence studies on thyroid dysfunction in HF patients ........................... 9
Table 3. Classification of thyroid dysfunction .............................................................................. 16
Table 4. Sociodemographic characteristics of ambulatory HF patients ...................................... 20
Table 5. Clinical characteristics of ambulatory HF patients .......... Error! Bookmark not defined.
Table 6. Prevalence of thyroid dysfunction in ambulatory HF patients according to respondents'
social and clinical characteristics..............................................................................24
Table 7. Thyroid dysfunction subtypes..........................................................................................25
Table 8. Association between thyroid dysfunction and severity of HF in ambulatory HF
patients.......................................................................................................................26
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Figure 1. Patterns of thyroid function tests and their cause............................................................5
Figure 2. Prevalence of thyroid dysfunction in ambulatory HF patients by age............23
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ABSTRACT
Background: Thyroid disorder affects 5–10% of the general population and can contribute to
heart failure (HF). Hypothyroidism leads to a decrease in the cardiac output by 30–50%. HF
affects 23 to 37 million people worldwide. However, despite the known relationship between
thyroid dysfunction and HF, there is still a paucity of evidence on the burden of thyroid
dysfunction in HF and their association in the Kenyan population. Knowledge of the burden of
thyroid dysfunction in HF is essential in guiding clinical decision making and improving
outcomes in HF patients.
Objectives: To determine the prevalence of thyroid dysfunction and its correlation with the
severity of HF in ambulatory HF patients attending adult outpatient clinic at Kenyatta National
Hospital (KNH).
Methods: A descriptive cross-sectional study design of ambulatory patients with HF attending
the outpatient cardiac clinic at the KNH. Ambulatory HF patients with a diagnostic label of HF
based on Framingham’s criteria were consecutively sampled. Patients with structural heart
disease based on echocardiogram findings, on amiodarone, and those who declined consent were
excluded from the study. The study included patients above 18 years. Chemiluminometric assay
was used to measure free triiodothyronine, free thyroxine, and thyroid stimulating hormones
(TSH) levels using the Liaison test kits. Thyroid function was defined as either normal or
abnormal based on thyroid function test at reference of: fT3 (2.2–4.2) pg/ml, fT4(0.8–1.7) ng/dl,
TSH (0.3–3.6) Uiu/ml. The sample was characterised, and overall prevalence, percentages,
mean, and standard deviation used. Association between severity of HF based on the New York
Heart Association functional class, class 1 and 2 (early HF), class 3 (advanced HF) and thyroid
dysfunction were assessed using Pearson’s chi-square test.
Results: 304 patients were sampled, 2 declined consent and 302 were recruited into the study.
Most of the HFs were caused by Hypertensive heart disease (HHD) (53.3%) and Dilated
cardiomyopathy (DCM) (30.8%). 76.2% had HF in class I and II. The overall prevalence of
thyroid dysfunction was 36.8% (95% CI: 31.5–42.4). Of those with thyroid dysfunction 66.7%
(95% CI: 57.1–75.3) were women and 33.3% (95% CI: 24.7–42.9%) were men. Older adults had
a higher prevalence of thyroid dysfunction with 49.6% (95% CI: 39.9–59.2) and 23% (95% CI:
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15.9–32.4) among those aged 65–79 years and 50–64 years respectively; 78.4% of patients with
thyroid dysfunction are 50 years and above. Prevalence of thyroid dysfunction was 28.8 % (95%
CI: 20.6–38.2), 41.4% (95% CI: 32.2–51.2) and 29.7% (95% CI: 21.4–39.1) for patients in HF
class III, II and 1, respectively.
Subclinical hypothyroidism (SCH) (18.8%, 95% CI: 14.6–23.8), euthyroid sick syndrome (9%,
95% CI: 6.0–12.7) and primary hypothyroidism (6%, (95% CI: 3.8–9.7) were the most prevalent
thyroid dysfunction subtypes. Secondary hyperthyroidism (1.0%, 95% CI: 0.3–3.1), subclinical
hyperthyroidism (1.0%, 95% CI: 0.3–3.1), primary hyperthyroidism (0.3%, 95 % CI: 0.1–1.8)
and free T3 toxicosis (0.3%, 95% CI: 0.1–1.8) were the least subtypes of thyroid disorders.
There was no significant association between thyroid dysfunction and severity of HF based on
NYHA functional class.
Conclusion: Prevalence of thyroid dysfunction in ambulatory HF patients is high. The most
common subtype of thyroid dysfunction is hypothyroidism, with SCH being the most prevalent
subtype. There is no significant association between thyroid dysfunction and severity of HF
based on NYHA functional class.
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1.1 Introduction
Heart failure (HF) affects 23 to 37 million people worldwide (1,2). Thyroid disorder affects
5–10% of the general population (3). Thyroid dysfunctions have a higher prevalence among
females, but with an increasing prevalence among males with advancing age (3). Among HF
patients, 21%–33.3% are estimated to have thyroid dysfunction (4).
Thyroid dysfunction is related to the development of HF (5-7). Hypothyroidism and
hyperthyroidism alter cellular and molecular pathways and lead to myocardial remodelling
and HF (5). Overt and subclinical hyperthyroidism is linked to an elevated risk of HF and
atrial fibrillation (7-10). Exposure of excess thyroid hormones leads to arterial stiffness,
decreased blood pressure and increased heart rate (7-10). Hyperthyroidism is correlated with
palpitations, tachycardia, exercise intolerance and exertional dyspnoea (11).
Hypothyroidism leads to a 30–50% decrease in cardiac output (12), an increase in hospital
admission and deaths among HF patients (13). Overt and SCH are associated with
bradycardia, mild hypertension, increased systemic vascular resistance and fatigue (13).
1.2 Problem Statement
Thyroid dysfunction can lead to HF (5-7). It can lead to atrial fibrillation resulting in acute
decompensation of the HF (7). Hypothyroidism has been associated with mortality increase
and hospitalization among HF patients (13). However, despite the known relationship
between thyroid dysfunction and HF, there is still a paucity of evidence on the burden of
thyroid dysfunction in HF and their association in the Kenyan population. Knowledge of the
burden of thyroid dysfunction in HF is essential in guiding clinical decision making and
improving outcomes in HF patients.
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2.1 HF
HF occurs when the heart is unable to pump blood at a rate equal with the metabolic
requirements of the body. HF (HF) affects approximately 26 million globally, 5.7 million in
the United States (14). Approximately 1936 per 100,000 population have HF in North
America and 248 per 100,000 population in Africa (15). The 10 year prevalence of
congestive HF is estimated to increase in the Caribbean and Latin America by 44%, 37% in
Asia-Pacific and 22% in Europe from 2016. (15). In the UK, the proportion of newly
diagnosed HF rose by 12% between 2002 and 2014 with a 23% prevalence during the period
(16). The prevalence of HF is high among those above 65 years of age (17). The mean age of
HF patients is estimated at 36-62 years in Sub-Saharan Africa (SSA) (18) and 59 years
globally (19). In SSA, hypertensive heart disease is the major cause of HF at 39.2%, dilated
cardiomyopathy 22.7%, rheumatic heart disease 13.8% and ischemic heart disease 7.2% (18).
In SSA, HF contributes to approximately 30% of hospitalisation in cardiovascular unit (20).
At KNH 5.7% of patients are admitted in acute HF (21). The mean age of hospitalised
patients at KNH is 44 years (21). The mean length of stay is 6.84 days ( 2-27 days) for
patients in Kenya (21). About 45.4% of the HF admissions in SSA are due to hypertension,
14.3% rheumatic heart disease, 7.7% ischaemic heart disease and 18.1% cardiomyopathy
(22). Most HF patients in SSA have a median hospital stay of 7 days (5–10 days) (22). In
addition, most of the patients present with comorbidities such as renal dysfunction (7.7–11%)
(19, 20, 22), diabetes (11.4–29%) (19, 22), HIV (Human immunodeficiency virus) (13%)
(22), hypertension (64%) (19), anaemia (15.2%) (22), and atrial fibrillation (18.3%) (22).
Globally, HF is estimated to cause 16.5% of all deaths with 34% and 23% of the deaths being
in Africa and India respectively (19). In SSA, HF causes deaths of 3.9%–25.2% of patients in
hospital (22-24). At KNH, mortality is 10.7 % among patients with acute HF (21). The 5-
year survival rate is estimated at between 50%–60% in most high-income countries (17).
HF is managed using loop diuretics, aldosterone antagonists, angiotensin converting enzyme
inhibitors and angiotensin receptor blockers (ACEI/ARBs), digoxin, loop diuretics, beta
blockers, angiotensin receptor neprilysin inhibitors (ARNI) (22, 23,25). The management
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involves prevention and control of modifiable risk factors like alcohol and tobacco use,
elevated blood glucose and blood pressure and physical inactivity (26).
HF costs an estimated $108 billion per annum globally with a per capita cost of $24/annum
in 2012 (27). High income countries (HIC) spend more on direct costs while Low and middle
income countries ( LMICs) on indirect cost (27).
2.2 Thyroid Dysfunction
Five to ten per cent of the general population have thyroid disorder, females have a higher
prevalence. Thyroid hormone metabolic dysfunction can lead to HF. Hypothyroidism and
hyperthyroidism alter the cellular and molecular pathways and lead to myocardial
remodeling and HF.
2.2.1 Prevalence and Patterns of Thyroid Dysfunction
Thyroid dysfunction in Africa occurs in 1.2% - 9.9% of the general population (28). In
Ethiopia, the prevalence of thyroid dysfunction among patients with an anterior neck mass is
65.2%, with the most prevalent subtype being SCH at 19.2% (29). In Europe, 6.7% of the
population has undiagnosed thyroid dysfunction. All the types of thyroid dysfunctions were
more common among females than males (28). In Germany, the prevalence increased from
7.6% to 18.9% between 2000 and 2010 (30). The prevalence of thyroid medication use and
goitre in Germany increased from 6.2% to 11.1% and decreased from 35.1% to 29.4%
respectively (30). In Cambodia, the prevalence is estimated at 24.5% (31) while the
prevalence is estimated at 26% with one male for every five females having a thyroid
dysfunction in Nepal (32). The prevalence is estimated at 31.2% in a Nigerian study on
patients who underwent a thyroid function test (33).
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2.2.2 Hyperthyroidism
Overt primary hyperthyroidism is a low serum TSH concentration and a high serum free
thyroxine concentration (34). The age of onset and duration of severity of thyroid hormone
dysfunction determines the clinical manifestations (34, 35).
In Europe, a meta-analysis estimated the prevalence of undiagnosed hyperthyroidism at 1.7%
and incidence rate at 51 per 100000 per year (36). The prevalence of hyperthyroidism was
estimated at 0.6% in Cape Town, South Africa with approximately 67% being undiagnosed
cases (37). In Nigeria, the subclinical and overt hyperthyroidism is estimated at 4.1% (0.8%
in males and 3.4% in females) and 13.7% (1.5% in males and 3.4% in females) respectively
(33). Euthyroid hyperthyroxinaemia and euthyroid sick syndrome is estimated at 0.3% and
1.5% (33).
Hyperthyroid patients are diagnosed using both clinical (history taking and physical
examination) and biochemical manifestations of the disease. The thyroid function tests are
the main laboratory test needed but some patients require a lipid profile due to tendencies by
hyperthyroid patients to have low cholesterol levels (35, 38). Physical examination of a
hyperthyroid patient will reveal increased size of the thyroid gland, stare and lid lag, warm
and moist skin and tachycardia with tremors and limitation of eye movement (35, 38).
Patients with overt hyperthyroidism have many manifestations that vary ,increased appetite,
weight loss, tremors and palpitations, weakness, and anxiety (35, 38). Mild hyperthyroidism
shows few localized and one-organ symptoms including weight loss, myopathy,
gynecomastia, and menstrual disorders (3, 35-39). Hyperthyroid patients tend to have low
total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) due to
increased metabolism of lipids and fatty acid clearance (3, 39). Table 1 outlines the
diagnostic criteria for different patterns of thyroid dysfunctions.
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Figure 1. Patterns of thyroid function tests and their causes
Table 1. Diagnostic criteria for hyperthyroidism subtypes
Hyperthyroidism Subtypes Diagnostic Criteria
‘Overt hyperthyroidism’ “Low serum TSH; High free T4 and/or T3”
‘T3-toxicosis’ “High serum T3”
“T4-toxicosis” “Low TSH; High serum free T4; Normal T3”
“Subclinical hyperthyroidism” “Low serum TSH; Normal serum free T4, T3 and free T3”
‘TSH-induced hyperthyroidism’ “Normal or high serum TSH; High free T4 and T3”
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2.2.3 Hypothyroidism
Overt hypothyroidism has a global cumulative incidence of 33–55% (40). The risk of
developing overt hypothyroidism is high among people with history of thyroid problems,
those on thyroid dysfunction inducing drugs, older (>60 years), anti-thyroid peroxidase
antibody and high initial TSH (>10 mU/L) (41). In a study of prenatal screening for overt
hypothyroidism, 2 per 1000 women had overt hypothyroidism (42).
2.2.4.1 Subclinical Hypothyroidism (SCH)
SCH is asymptomatic normal serum free thyroxine concentration in presence of an elevated
serum TSH concentration (43). It is caused by Hashimoto’s thyroiditis, external radiation
therapy in blood cancers, and inadequate T4 replacement therapy (43). In 2–28% of the
cases, it progresses to overt hypothyroidism (40, 45), and is associated with coronary heart
diseases (10), HF and stroke (44) and cardiovascular mortality (45, 46). It is also associated
with abnormalities of the reproductive health system such as amenorrhoea and
oligomenorrhoea (47), non-fatty liver disease and neuropsychiatric symptoms (48, 49). In
Taiwan, a study found that hypothyroidism is associated with reduced estimated glomerular
filtration rate (eGFR) with a higher risk for developing chronic kidney disease (CKD) than
euthyroid patients (50).
In a pregnancy loss hypothyroidism study, 8.4% and 3.1% of the women had subclinical and
undiagnosed overt hypothyroidism (51). The prevalence of SCH is 30.6% among patients
with CKD on haemodialysis in Karachi, being higher among females (46.2%) and those aged
40 years and above (46.2%) (52). Among a sample of 12,900 patients with SCH in the
United Arabs Emirates, 6.5% progressed to overt hypothyroidism over 10-years (53).
Treatment of hypothyroidism focuses on improving symptoms, normalizing TSH secretion,
reducing the size of the goitre and avoiding overtreatment (54). Synthetic thyroxine is the
treatment of choice (54).
2.2.4.2 Drug induced Thyroid Dysfunction
Drug use could result in altered thyroid metabolism and reduce TSH levels in the body. High
doses of glucocorticoids, dopamine/dobutamine, imatinib, and octreotide can lower the level
of TSH but do not cause clinically significant thyroid dysfunction. Antiepileptic medications
such as carbamazepine reduce the triiodothyronine (T3) and thyroxine (T4) half-lives,
oestrogens reduce free thyroxine (FT4) availability while glucocorticoids and amiodarone
inhibit or impairs the deionisation of T4 to T3 (55, 56). Amiodarone, a drug used to treat
cardiac arrhythmias, with a 50-100 days elimination half-life can cause amiodarone-induced
thyrotoxicosis or hypothyroidism (12, 57).
2.2.4.3 Laboratory Evaluation of Thyroid Function
The thyroid hormone controls the TSH, which regulates the secretion of thyroxine and
triiodothyronine (38). Thyroid function is measured best using the serum TSH since serum
free T4 and TSH have a negative log-linear relationship. However, either one or more of the
serum TSH, serum total T4, serum total T3 and serum free T4/T3 concentrations could be
used to assess thyroid function.
TSH concentration are measured using chemiluminometric assays, which have a detection
limits of 0.01mU/L and thus able to detect mild hyperthyroidism and distinguish overt
hyperthyroidism from euthyroid patients. The serum total T4 and T3 can be measured using
the chemiluminometric assays and RIA (Radioimmunoassay) among other immunoassays.
Serum T4 Is bound to thyroxine-binding globulin while serum T3 is bound more on albumin
than thyroxine-binding globulin.
The thyroid function test is used clinically to screen patients at risk or strongly suspected to
have thyroid dysfunction, monitor treatment of hyperthyroidism, and assess the adequacy of
levothyroxine therapy. The thyroid function test helps adjust levothyroxine replacement
therapy effectively in patients with primary hypothyroidism and thyroid cancer.
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2.3 Thyroid Dysfunction and HF
Hypothyroidism leads to a cardiac output decrease by 30–50% (12). Overt and SCH is linked
to bradycardia, fatigue, death and hospital admissions in HF patients (13). A one-fifth to a
third of HF patients have thyroid dysfunction (4,58) while 4% to 35% have SCH (4,59). A
prospective study of 114 HF patients found a prevalence of 30% in India (60). Patients with
HF tend to have a higher prevalence of SCH than hyperthyroidism (4, 5, 58, 60). Table 2
summarises some of the prevalence studies on thyroid dysfunctions among HF patients.
Thyroid hormone has significant effects to the cardiovascular system increasing the heart
rate, cardiac output, oxygen consumption in the myocardium and diastolic relaxation (3, 59).
The actions of T3 can produce adrenergic effects and inotropic and chronotropic stimulation.
Hyperthyroidism causes a reduction of phospholamban and systemic vascular resistance and
increases the myocardial sarcoplasmic reticulum calcium-dependent ATP (Adenosine
triphosphate) resulting in cardiac output increase, diastolic relaxation, and cardiac
contractility (6).
Hyperthyroidism is also related to an increase in other cardiovascular disorders such as
hypertension, HF, and angina. Hyperthyroid patients have premature supraventricular
depolarizations, and tachycardia. Unmanaged atrial fibrillation in hyperthyroid patients
complicates to HF (3, 6, 59).
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Table 2. Summary of prevalence studies on thyroid dysfunction in HF patients
Country Study Design Sample
Low T3 syndrome – 34%
Subclinical hyperthyroidism – 2%
SCH – 14.4%
America, Canada,
Low T3 syndrome – 4%
2.3.1 Hyperthyroidism and HF
Hyperthyroidism results in a rate-related cardiomyopathy among patients with HF with no
underlying cardiac condition (62). Overt hyperthyroidism has been associated with
pulmonary hypertension (44). Hyperthyroidsm increases the risk of atrial fibrillation (7).
About 10%–25% of hyperthyroid patients have atrial fibrillation, majority of these being
above 60 years (63). Hyperthyroidsm is associated with coagulation abnormalities increasing
the risk of cardiac blood clot formation in patients (64).
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2.3.2 Hypothyroidism and HF
Hypothyroidism causes a 30–50% decrease in cardiac output (12), increased mortality and
hospitalization in HF patients (13). Hypothyroidism almost has an opposite effect on the
heart compared to hyperthyroidism. Reduced cardiac contractility in hypothyroid patients
results in reduced ventricular diastolic relaxation and decreased cardiac output (12, 62, 63).
Patients with hypothyroidism show the following clinical manifestations of cardiovascular
disease: bradycardia, non-pitting oedema, pericardial effusions, hypertension and exertional
dyspnoea and exercise intolerance (12, 62, 63).
Furthermore, the hypothyroid patients tend to have high cholesterol levels. The elevated
cholesterol levels as well as the diastolic hypertension among other factors increase the
likelihood of coronary heart disease (64, 65). Hypothyroid patients have decreased LDL
catabolism. These patients also have increased oxidation of LDL, and decreased cholesterol
secretion into bile and transfer of cholesteryl ester (64).
2.3.3 Outcome of Thyroid Dysfunction in HF
The risk of mortality is increased 1.58 times in patients with symptomatic HF and abnormal
thyroid function (13) relative to those without thyroid dysfunction. Also, HF patients are
known to have poor prognosis when diagnosed with SCH (7, 66). A study found that the
likelihood for mortality and admissions to hospital is increased in patients with SCH and HF
(67). HF progression is increased significantly among patients with hypothyroidism (68).
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2.4 Study Purpose
The aim of the study was to determine the burden of thyroid dysfunction and its association
with the severity of HF in ambulatory HF patients attending adult outpatient cardiac clinic at
KNH.
2.5 Study Significance
The proportion of HF patients has increased over the years forming…